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Biomedical subjects

J A Roth

Publications and source records attributed to J A Roth.

At least 181 records · Page 10Linked to original sources
PubMed1996

Gene therapy for lung cancer: enhancement of tumor suppression by a combination of sequential systemic cisplatin and adenovirus-mediated p53 gene transfer.

A more effective gene therapy strategy for lung cancer using sequential cisplatin administration and adenovirus-mediated p53 gene transfer was developed on the basis of our previous observation of enhanced expression of a reporter gene in malignant cells exposed to cisplatin before gene transfer. Transfer of the normal (wildtype) p53 gene into cisplatin-treated H1299 cells, in which p53 is homozygously deleted, resulted in up to a 60% further inhibition of cell proliferation in vitro than p53 transfer into untreated H1299 cells. The cisplatin plus p53 gene transfer strategy yielded significantly greater apoptosis and tumor growth suppression in an animal model of subcutaneous H1299 tumor nodules than wildtype p53 gene transfer alone. The timing of cisplatin administration and p53 gene transfer was shown to be critical: cisplatin administration simultaneous with or subsequent to p53 gene transfer was less effective than cisplatin-first sequential treatment. Moreover, the in vivo inhibition of tumor growth was maintained by repeated cycles of treatment. This gene therapy strategy has been incorporated into a phase I clinical trial for the treatment of lung cancer and provides a basis for the development of improved therapeutic protocols.

Animals↗
PubMed1996

Mutations of p53 in Barrett's esophagus and Barrett's cancer: a prospective study of ninety-eight cases.

We had previously identified p53 mutations in Barrett's esophagus and therefore began a multiinstitutional study to determine their significance as a marker for malignancy. Ninety-eight patients from four institutions were studied. Forty-eight patients (37 men and 11 women, mean age 56.2 years) had Barrett's esophagus with metaplasia or dysplasia but no evidence of malignancy at a mean follow-up of 2.2 years. Barrett's esophagus was classified as metaplasia with no evidence of dysplasia in 32 patients, as low-grade dysplasia in 13, and as high-grade dysplasia in three. The other 50 patients (46 men and four women, mean age 60.2 years) had adenocarcinoma arising in Barrett's esophagus. Tissues from normal stomach or esophagus, tumor, and Barrett's esophagus were obtained for deoxyribonucleic acid analysis by endoscopic biopsy from patients with Barrett's esophagus or cancer or during operations on some patients with Barrett's cancer. Exons 5 through 9 of the p53 gene were studied for mutations by single-strand conformational polymorphism analysis after polymerase chain reaction amplification. Mutations detected by single-strand conformational polymorphism analysis were confirmed by deoxyribonucleic acid sequencing. None of the tissue samples from patients with Barrett's esophagus alone and no dysplasia or low-grade dysplasia had any p53 mutations, but one of the three patients with high-grade dysplasia and no evidence of invasive malignancy did have a p53 mutation. Of the 50 patients with Barrett's cancer, however, 23 (46%) had p53 mutations in Barrett's epithelium, tumors, or both. Twenty of these patients had p53 mutations in the tumor only (n = 16) or in both tumor and Barrett's epithelium (n = 4), suggesting that the mutation plays a direct role in carcinogenesis. Mutations in Barrett's epithelium were found in one patient in the group without malignancy and in seven patients with cancer (one with no dysplasia, two with low-grade dysplasia, and five with high-grade dysplasia). In three patients with cancer, mutations occurred only in Barrett's epithelium, suggesting that such mutations may also be a marker for genomic instability. Mutations were predominantly found in exons 5, 7, and 8, and transitions from guanine to adenine were the most frequent changes. Mutations of p53 are clearly involved in the pathogenesis of Barrett's cancer for a subset of patients (46%), and the fact that we could detect mutations in premalignant Barrett's epithelium supports the hypothesis that p53 mutations may be a useful marker for patients at increased risk for development of invasive cancer.

Adenocarcinoma↗
PubMed1996

Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer.

A retroviral vector containing the wild-type p53 gene under control of a beta-actin promoter was produced to mediate transfer of wild-type p53 into human non-small cell lung cancers by direct injection. Nine patients whose conventional treatments failed were entered into the study. No clinically significant vector-related toxic effects were noted up to five months after treatment. In situ hybridization and DNA polymerase chain reaction showed vector-p53 sequences in posttreatment biopsies. Apoptosis (programmed cell death) was more frequent in posttreatment biopsies than in pretreatment biopsies. Tumor regression was noted in three patients, and tumor growth stabilized in three other patients.

Aged↗
PubMed1996

Preoperative chemotherapy for stage IIIa non-small cell lung cancer.

About 20% of patients with non-small cell lung cancer are stage IIIa at diagnosis. The treatment of stage IIIa tumors has been discouraging. Long-term disease control and cure rates with a single modality approach with surgery or radiotherapy have been poor; this is particularly so for N2 tumors, which account for the majority of stage IIIa disease. In the past decade there has been interest in multimodality treatment of stage IIIa non-small cell lung cancer using preoperative induction chemotherapy with or without radiotherapy followed by surgery. Several phase II studies and two small phase III trials have shown that a strategy of induction chemotherapy with or without radiotherapy is feasible and probably does offer some survival advantage over surgery or radiotherapy alone. The next issue to be tackled is to determine whether the results achieved with induction chemoradiation followed by surgery are equivalent to those of chemoradiation without surgery. A phase III intergroup trial is underway to answer this question.

Antineoplastic Agents↗
PubMed1996

An atypical T-cell lymphosarcoma in a calf with bovine immunodeficiency-like virus infection.

An 11-month-old Holstein calf experimentally infected with bovine immunodeficiency-like virus (BIV) developed T-cell lymphosarcoma 5 months postinoculation, concurrent with progressive monocytosis. Tumors were found in the thymus, multiple lymph nodes, and brain. Tumor cells were CD2+, CD4-, CD8-T cells. Infectious BIV could be recovered from splenic tissue and blood mononuclear cells. Bovine leukemia virus was not present. Because this calf was part of an ongoing experiment on the pathogenesis of BIV infection, immune function data were also available both before and after lymphosarcoma developed. Neutrophil and monocyte function were normal, but lymphocyte blastogenesis was enhanced before the development of lymphosarcoma. Follicular hyperplasia in lymphoid tissues was also seen. This case raises the possibility that BIV infection may cause or be associated with some cases of atypical T-cell lymphosarcoma, without evidence of immune suppression at the time of tumor onset.

Animals↗
PubMed1996

Antisense regulation of oncogenes in human cancer.

Gene transfer or manipulation of genes for the treatment of cancer is a rapidly expanding field. In recent years, much attention has been focused on manipulating cancer genes and applying antisense technology in therapeutic ways. Consequently, antisense RNA control is now recognized as a specific means of regulating gene expression at the posttranscriptional level. Defects in vital genes occur in many human diseases, including cancer, defects that may be due to an accumulation of mutations in the genes that leads to the production of faulty proteins. Although the biological significance of such mutant proteins still remains in question, recent experiments have demonstrated that genes overproducing faulty proteins are often associated with increased tumor cell growth. Moreover, using a stretch of antisense RNA to block the production of such defective proteins can effectively silence their genes; as a result, tumor cells stop dividing rapidly and revert to a more normal phenotype. Therefore, antisense RNA technology could have a significant impact on cancer gene therapy. Here, we have tried to give comprehensive coverage to some major cases of antisense RNA control of cancer-related genes highlighting the biological systems involved, the efficacy of the antisense RNA in altering target gene function, and how such antisense control affects the malignant phenotype. Furthermore, the therapeutic potential of the antisense technique depends on the in-depth understanding of the target gene function and its role in carcinogenesis.

Animals↗
PubMed1996

Gene replacement strategies for cancer.

The strategy for the inactivation or replacement of cancer-causing genes is analogous to the classic concept of gene therapy for replacement of defective or nonfunctioning genes. The gene families implicated in carcinogenesis include dominant oncogenes and tumor suppressor genes. Regional administration of viral vectors expressing wildtype p53 and antisense K-ras prevents growth for tumors with the specific genetic lesions in orthotopic tumor models and mediates regression of large established tumors. These studies provide a rationale for a new clinical protocol recently approved by the United States National Institutes of Health (NIH) Recombinant DNA Advisory Committee and the Federal Drug Administration (FDA) to replace a defective p53 gene with intratumor injection of recombinant retrovirus expressing normal p53 and to inactivate mutant K-ras by expression of antisense K-ras mRNA. If these agents are efficacious, their lack of toxicity may provide a sufficiently high therapeutic index such that they could be used as an adjuvant to surgery to treat patients with earlier stages of cancer or as prevention for second primary cancers for individuals with genetic abnormalities in premalignant lesions. Although much research needs to be done, the possibility of specific gene targeting with a high therapeutic index makes this a promising area for investigation.

Genes, Tumor Suppressor↗
PubMed1996

Comparison of burst pacing, autodecremental (ramp) pacing, and universal pacing for termination of ventricular tachycardia.

This study was designed to test the comparative efficacy of burst pacing, autodecremental (ramp) pacing, and universal (steep ramp) pacing for termination of ventricular tachycardia. A prospective, randomized sequence cross-over design was used to achieve comparisons of the pacing modalities that were matched for patient, day, and ventricular tachycardia characteristics. Thirty eight patients were enrolled, whose ventricular tachycardia was well-enough tolerated to be reinduced, and tested with 3 pacing modalities. There were 27 series 1 patients in which the pacing modalities were nonsynchronized burst pacing, synchronized burst pacing, and ramp pacing. The 11 patients in series 2 were tested with synchronized burst pacing, ramp pacing, and universal pacing. All pacing methods proved to be comparable in their ability to terminate ventricular tachycardia (p = NS). The 2 burst methods required the fewest number of attempts (significant vs ramp pacing). Universal pacing required the fewest number of stimuli. The mean paced cycle length was similar will all methods. The shortest paced cycle lengths were found with the autodecremental and universal methods because of their ramp patterns. It is concluded that burst, ramp, and universal pacing are of similar efficacy, although ramps were least efficient. Choice of a modality depends on operator preference, and individual patient response.

Cardiac Pacing, Artificial↗
PubMed1996

In vitro lymphocyte proliferative responses and gamma-interferon production as measures of cell-mediated immunity of cattle exposed to Pasteurella haemolytica.

Cell-mediated immune mechanisms may play a role in the pathogenesis and prevention of pneumonia in cattle caused by Pasteurella haemolytica serotype A1. To determine the circumstances required to stimulate and identify cell-mediated immune responses, calves were vaccinated with a commercial P. haemolytica bacterin or a live commercial P. haemolytica vaccine, or were infected intratracheally with virulent P. haemolytica. All calves were challenge-exposed intratracheally with P. haemolytica 31 d after vaccination or prior infection. Peripheral blood mononuclear cells and mediastinal and superficial cervical lymph node cells were stimulated with antigens prepared from P. haemolytica to evaluate in vitro proliferative responses and gamma-interferon production as measures of cell-mediated immunity. Strong proliferative responses and gamma-interferon production were detected in lymph node cells from calves vaccinated with the live vaccine and from infected calves, especially in response to stimulation with an outer membrane protein preparation from P. haemolytica. Greater proliferative responses and gamma-interferon production were associated with the lymph node nearer the site of bacterin administration (superficial cervical lymph node) or the site of infection (mediastinal lymph node), whereas greater proliferative responses and gamma-interferon production were associated with the more distant lymph node (mediastinal lymph node) in calves vaccinated with the live vaccine. Neither proliferative responses nor gamma-interferon production were detected in peripheral blood mononuclear cells from calves that were vaccinated for or infected with P. haemolytica. Antileukotoxin antibody titers were determined by a serum neutralization assay, and protection against pneumonic lesions was more closely correlated with antileukotoxin antibody responses than with lymphocyte proliferation or gamma-interferon responses.

Animals↗
PubMed1996

[Recombinant virus-mediated transfer of the wild-type p53 gene is a potent therapeutic strategy for human cancer].

Tumor suppressor p53 gene, which is most commonly mutated in human cancers, plays an important role in the control of cell cycle and the induction of apoptosis (programmed cell death). Transfection of the wild-type p53 gene into tumor cells induced either growth suppression or apoptosis. We have examined the effect of the recombinant retroviral or adenoviral vector expressing the wild-type p53 gene on the tumor cell proliferation as well as on the sensitivity of infected-tumor cells to various anticancer agents. The possible application of recombinant virus-mediated direct in vivo transfer of the wild-type p53 gene to human cancer therapy will be discussed.

Adenoviridae↗
PubMed1996

Evaluation of topical gene therapy for head and neck squamous cell carcinoma in an organotypic model.

The organotypic (raft) culture system has been shown to be a useful model for examining the effects of biochemical manipulations on various epithelial cell types, using in vitro conditions that simulate the in vivo environment of the tissue of origin. To investigate this method as a model for topical gene therapy, we cultured the oral head and neck squamous cell carcinoma cell line TR146 on fibroblast-containing collagen gels at the air-medium interface and assessed the efficiency of transduction of a topically applied adenoviral vector containing beta-galactosidase cDNA. Diffuse expression of -galactosidase activity in multiple cell layers demonstrated effective penetration of the vector. Transduction efficiency and therapeutic activity of a replication-defective recombinant adenovirus containing wild-type p53 cDNA linked to a FLAG marker (AdCMV-p53-FLAG) were then assessed in TR146 organotypic cultures transduced by topical application. Twenty-four, 48, and 72 h after transduction, the cultures were harvested, and residual cell number and FLAG peptide expression were determined. The number of cells in p53 transduced cultures was significantly reduced in comparison to controls at all three time points (P < 0.001), which resulted from the induction of apoptosis as determined by in situ DNA end labeling. In addition, the FLAG peptide was expressed diffusely in the residual cells, further confirming effective transduction and expression of the exogenous gene products throughout multiple layers. We conclude that the organotypic culture is an effective in vitro model for assessing the efficacy of topically applied gene therapy on head and neck squamous carcinomas and premalignancies.

Adenoviridae↗
PubMed1996

Adenoviral-mediated wild-type p53 gene expression sensitizes colorectal cancer cells to ionizing radiation.

Wild-type p53 gene transfer into the SW620 colorectal carcinoma cell line was performed using the replication-defective adenovirus Ad5/CMV/p53 to evaluate the effect of wild-type p53 expression on radiation sensitivity. The results indicated that infection with Ad5/CMV/p53 sensitized the cells. The survival at 2 Gy was reduced from 55 to 23%. Flow cytometric analysis of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay-labeled cells and in situ TUNEL staining of xenograft tumors demonstrated an increase in labeled cells with combination treatment, indicating increased apoptosis in cells treated with Ad5/CMV/p53 before irradiation. A significant enhancement of tumor growth suppression by this combination strategy was observed in a s. c. tumor animal model compared to p53 gene therapy alone. The delay in regrowth to control tumor size of 1000 mm3 was 2 days for 5 Gy, 15 days for Ad5/CMV/p53, and 37 days for Ad5/CMV/p53 + 5 Gy, indicating synergistic interactions. These data indicate that the delivery of wild-type p53 to cells with p53 mutations increases their radiation sensitivity, and this may be accomplished by adenoviral-mediated gene therapy.

Adenoviridae↗
PubMed1995

Evaluation of end points of serial drug testing in patients with sustained ventricular tachycardia after healing of acute myocardial infarction.

Serial electrophysiologic drug testing was used to guide antiarrhythmic therapy in a consecutive series of 150 patients with clinical sustained ventricular tachycardia (VT) or cardiac arrest and inducible monomorphic VT. All patients had coronary artery disease and a history of myocardial infarction. For patients with clinical sustained VT, drug responders and partial drug responders (VT slowed by drug to rate < 150 beats/min, with systolic blood pressure > or = 90 mm Hg) had similar total mortality rates (2-year actuarial survival 100% and 94%, p = NS), which were statistically different from that of patients with drug inefficacy (2-year survival 67%). Partial drug responders had high arrhythmia recurrence rates, similar to those of patients with drug inefficacy. For cardiac arrest survivors, the results of electrophysiologically guided drug testing did not predict prognosis. Patients with a change in mode of VT induction during antiarrhythmic therapy had a favorable prognosis (no deaths during follow-up).

Adult↗
PubMed1995

Altered expression of the p50 subunit of the NF-kappa B transcription factor complex in non-small cell lung carcinoma.

Recent studies have implicated a role for the p50 subunit of the NF-kappa B transcription factor complex in tumorigenesis. Therefore, we investigated the expression of the p50 subunit of the NF-kappa B transcription factor complex in paired normal and non-small cell lung carcinoma (NSCLC) tissues. Here we show that nine of 11 (81.8%) fresh NSCLC tissues expressed from two- to 20-fold higher levels of the p50 subunit than normal lung tissue. Thirteen NSCLC cell lines also exhibited high levels of p50. Alterations in the normal NF-kappa B/rel pathway of regulation may play a role in the genesis of NSCLC.

Carcinoma, Non-Small-Cell Lung↗
PubMed1995

Cell cycle arrest and inhibition of tumor cell proliferation by the p16INK4 gene mediated by an adenovirus vector.

The p16INK4 (MTS1) gene has many features of a tumor suppressor gene. It maps to 9p21, a region of frequent loss of heterozygosity in a variety of tumor types. It encodes an inhibitor of cyclin-dependent kinase 4, and its homozygous deletion is common in tumor-derived cell lines. To examine its tumor suppressive function and its potential in cancer gene replacement therapy, wild-type p16INK4 was expressed in an adenovirus-derived gene delivery system and introduced into lung cancer cell lines that do not express p16INK4. Expression of the introduced p16INK4 blocked tumor cell entry into S phase of the cell cycle and inhibited tumor proliferation both in vitro and in vivo. These observations strongly support that p16INK4 is a tumor suppressor gene and is a candidate for cancer gene replacement therapy.

Adenoviridae↗
PubMed1995

Long-term outcomes and modes of death of patients treated with nonthoracotomy implantable defibrillators.

Long-term outcomes of all patients who underwent nonthoracotomy implantable cardioverter-defibrillator (ICD) implantation at our institution from April 1991 to October 1994 were studied using the intention-to-treat analysis. Of 94 consecutive patients, 81 underwent nonthoracotomy ICD implantation and 13 underwent thoracotomy (for concomitant surgery in 11 and unavailability of nonthoracotomy leads in 2). Six of 81 patients had a high defibrillation threshold, 4 subsequently underwent thoracotomy, and 2 were treated with amiodarone. Surgical mortality was 0%. The duration of follow-up was 20 +/- 13 months, and was > 12 months in 74% of 67 living patients. Actuarial survival rates at 1 and 2 years were, respectively, 98% and 94% for sudden death and 91% and 83% for total mortality. Deaths during long-term follow-up were mostly due to nonsudden cardiac or noncardiac deaths. Two-year mortality rates were 12% and 25% in patients with ejection fraction > or = 30% and < 30%, respectively. Thus, instances of sudden death and surgical mortality are very few in patients with nonthoracotomy ICDs. Deaths during long-term follow-up are mostly due to nonsudden cardiac and noncardiac deaths. Therefore, ICD therapy may have greater impact on survival in patients with lower risks of nonsudden cardiac and cardiac death (e.g., younger patients with minimal heart disease) than in patients with severe cardiac or noncardiac disease. Prospective studies are needed to address this question.

Actuarial Analysis↗